8-iso-prostaglandins for glaucoma therapy

ABSTRACT

The present invention relates to the use of 8-iso prostaglandins and their derivatives for decreasing intraocular pressure, for example in the treatment of glaucoma It is based, at least in part, on the discovery that 8-iso prostaglandin E 2  effectively decreased intraocular pressure by a trabecular meshwork outflow mechanism.

This application is a continuation of U.S. Ser. No. 08/853,803 filed May9, 1997 now abandoned.

INTRODUCTION

The present invention relates to the use of 8-iso prostaglandins andtheir derivatives for decreasing intraocular pressure, for example inthe treatment of glaucoma. It is based, at least in part, on thediscovery that 8-iso prostaglandin E₂ effectively decreased intraocularpressure by a trabecular meshwork outflow mechanism.

BACKGROUND OF THE INVENTION

Glaucoma is a major eye disease which can cause progressive loss ofvision leading to blindness. The majority of human glaucomas areassociated with increased intraocular pressure (“IOP”) resulting from animbalance in the rate of secretion of aqueous humor by the ciliaryepithelium into the anterior and posterior chambers of the eye and therate of aqueous humor outflow from these chambers, primarily via thecanal of Schlemm. High IOP is considered the major risk factor forglaucomatous visual impairment resulting from the death of retinalganglion cells, loss of the nerve fiber layer in the retina, anddestruction of the axons of the optic nerve. Current treatments aredirected toward reducing intraocular pressure.

Glaucoma is typically classified, on the basis of its etiology, asprimary or secondary. Primary glaucoma in adults, a disorder in whichthe underlying cause is poorly understood, is associated with increasedIOP due to an obstruction of aqueous human outflow. The obstruction maybe caused by a blockage located at the angle formed between the iris andthe lateral cornea, categorized as either open angle or acute or chronicangle closure. The anterior chamber of the eye appears normal in chronicopen angle glaucoma, despite impaired drainage of aqueous humor. Incontrast, the anterior chamber is shallow and the filtration angle isnarrowed in chronic angle-closure glaucoma, wherein the trabecularmeshwork and the canal of Schlemm may be obstructed by the iris. Anacute attack of glaucoma may arise in this context when the pupildilates, pushing the root of the iris forward to block the angle.

Secondary glaucoma is caused by another disorder which functionallyinterferes with the outflow of aqueous humor or the flow from theposterior to the anterior chamber. Such interference may be caused byinflammation, a tumor, an enlarged cataract, central retinal veinocclusion, trauma, or hemorrhage.

Several classes of drugs acting by different mechanisms are used astopically administered ocular therapy to lower IOP. These include betaadrenergic blockers (e.g., timolol), topical carbonic anhydraseinhibitors (e.g., dorzolamide), and alpha₂-adrenergic receptor agonists(e.g., clonidine derivatives), all of which act primarily by decreasingthe formation of aqueous humor within the eye. Pilocarpine andepinephrine are clinical agents that also lower IOP in glaucamatouseyes, but these drugs act principally by decreasing the resistance inthe trabecular meshwork outflow channels. A third mechanism for loweringIOP in the primate eye is by increasing the outflow of aqueous humor viathe uveoscleral route. Recently, a prostaglandin derivative belonging tothe F2α series of prostanoids, which acts primarily by this uveoscleralmechanism, has been introduced for glaucoma therapy. This drug, calledlatanoprost, is the isopropyl ester of a compound having the followingstructure:

Prostaglandins which may be used in the treatment of glaucoma aredescribed in U.S. Pat. Nos. 5,476,872 by Garst et al., 4,599,353 byBito, 5,262,437 by Chan, 5,462,968 by Woodward, 4,132,847 by Kuhla,5,173,507 by DeSantis et al., 5,578,618 by Stjernschantz et al.,5,208,256 by Ueno, 5,565,492 by DeSantis et al., 5,151,444 by Ueno etal., and PCT Application No. PCT/US93/10853, International PublicationNo. WO 94/11002 by Woodward.

The present invention relates to prostaglandins which are structurallydifferent from latanoprost and other prostaglandins used in thetreatment of glaucoma, and that belong to the 8-iso series ofprostanoids, for example 8-iso PGE₂, 8-iso PGE₂ and 8-iso PGF_(2α). Incontrast to latanoprost, 8-isoPGE₂ lowers IOP primarily by decreasingthe resistance to trabecular outflow of aqueous humor from the eye.

SUMMARY OF THE INVENTION

The present invention relates to the use of 8-iso prostanoids in methodswhich decrease intraocular pressure (“IOP”) in the eye, for example inthe treatment of glaucoma. The 8-iso-prostanoids of the invention have acommon structure according to formula I:

where either bond W or bond X can be a single or a double bond, Y iseither (i) a hydroxyl group having either α or β orientation relative tothe five-membered ring or (ii) a keto function at carbon 9, and Z is ahydrocarbon group which may be aliphatic (cyclic or non-cyclic),aromatic, or a combination of aliphatic and aromatic at carbon 16.

In a first nonlimiting embodiment of the invention, the 8-iso prostanoidis 8-iso prostaglandin E₂ (prosta-5,13-dien-1-oic acid,11,15-dihydroxy-9-oxo, (5Z, 8β, 11α, 13E,15S), having Formula II:

In a second nonlimiting embodiment of the invention, the 8-isoprostanoid is 8-iso, 5,6 dihydro prostaglandin E₂ (referred to as 8-isoPGE₁), having Formula II:

In a third nonlimiting embodiment of the invention, the 8-iso prostanoidis 8-iso PGF_(2α), (prosta-5,13-dien-1-oic acid, 9, 11, 15-trihydroxy-,(5Z, 8β, 9α, 11α, 13E, 15S)-, having Formula IV:

The present invention also provides for derivatives of compounds ofFormulas II, III or IV which retain basic Formula I and their use inmethods of decreasing intraocular pressure.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of 8-iso prostanoids havingbasic Formula I to decrease intraocular pressure in a subject in need ofsuch treatment. In specific nonlimiting embodiments of the invention,the 8-iso prostanoid may be selected from the group of (i) 8-isoprostaglandin E₂ (prosta-5,13-dien-1-oic acid, 11,15-hydroxy-9-oxo, (5Z,8β, 9α, 11α, 13E, 15S) (“8-iso PGE₂”), having Formula II; (ii) the 5,6dihydro derivative of 8-iso PGE₂, having Formula III and referred to as8-iso PGE₁; (iii) prosta-5,13-dien-1-oic acid, 9, 11, 15-trihydroxy-,(5Z, 8β, 9α, 11α, 13E, 15S) (“8-iso PGF_(2 α)”), having Formula IV; and(iv) derivatives of compounds having Formulas II, III or IV which retainbasic Formula I and which, when administered to the eye of a subjecthaving increased intraocular pressures, will decrease intraocularpressure by at least 10 percent.

The main structural differences between the 8-iso prostanoids of theinvention and latanoprost are the following: (i) the side chainsubstituents on the five-membered rings have the opposite geometricarrangement with respect to the plane of the ring (cis for the 8-isoprostanoids of the invention and trans for latanoprost); (ii) thefive-membered ring has a keto or hydroxyl function at position 9 in the8-iso prostanoids of the invention, whereas there is just a hydroxylgroup in the same position in latanoprost; and (iii) the side chainsbeginning with the sixteenth carbon may have different structures, as,for example, latanoprost containing a terminal methyl phenyl group atthis position. 8-iso prostanoid derivatives of the invention contain afive-membered ring and two side chains, and retain distinguishingfeatures (i)-(iii) as set forth in the preceding sentence and in FormulaI. In preferred embodiments, such derivatives are esters of compoundshaving Formula II, III or IV. For example, esterified derivatives of8-iso PGE₂ may be used according to the invention, and may provideimproved penetration into the eye.

The mechanism of action by which 8-iso PGE₂ lowers IO has been found tobe different from that of latanoprost in experiments done in primates,in that 8-iso PGE₂ has been found to increase trabecular outflowfacility by decreasing resistance to outflow of aqueous humor. This isan advantage in that the trabecular meshwork is the primary locus of thepathology causing increased IOP in primary open angle glaucoma.

Accordingly, the present invention provides for a method for decreasingIOP comprising administering a therapeutically effective amount of an8-iso prostanoid of the invention to a subject in need of suchtreatment. Such a method may be used in the treatment of glaucoma in asubject. Suitable formulations include for example, and not by way oflimitation, a topical solution which is a physiological saline solution,having a pH between about 4.5 and 8 and an appropriate buffer system(e.g., acetate buffers, citrate buffers, phosphate buffers, boratebuffers) a neutral pH being preferred. The formulation may furthercomprise a pharmaceutically acceptable preservative (e.g. benzalkoniumchloride, thimerosol, chlorobutanol), stabilizer and/or surfactant (e.g.Tween 80). The formulation may also comprise a compound which acts as ananti-oxidant (e.g. sodium metabisulfite, sodium thiosulfate,acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene). A“therapeutically effective amount” of an 8-iso prostanoid of theinvention refers to an amount of drug which decreases the IOP by atleast about 10 percent, preferably at least about 15 percent, and morepreferably at least about 20 percent. In particular embodiments of theinvention, the administration of 8-iso prostanoid results in an increasein trabecular outflow facility of at least about 10 percent, preferablyat least about 20 percent, and more preferably at least about 30percent. In nonlimiting embodiments of invention, a topical preparationof 8-iso prostanoid at a concentration of between 0.001 and 1 percent,preferably between 0.05 and 0.2 percent, and more preferably betweenabout 0.05 and 0.1 percent may be used.

According to the invention, IOP may be decreased, and/or glaucoma may betreated, using compositions comprising an 8-iso prostanoid of theinvention as the sole active agent, or in conjunction with anotheractive agent. For example, combination of 8-iso prostanoid and anotherdrug used to treat elevated intraocular pressure, including but notlimited to another prostaglandin derivative (including, but not limitedto, latanoprost), pilocarpine, epinephrine, a beta adrenergic agent(e.g., timolol), a carbonic anhydrase inhibitor (e.g., dorzolamide), oran alpha₂-adrenergic receptor agonist (e.g., a clonidine derivative),may be used.

EXAMPLE 1

Experiments were performed to evaluate the effects of single doseadministration of 8-iso PGE₂ an IOP in normal (“N”) and glaucomatous(“G”) monkey eyes, and to determine the mechanism by which 8-iso PGE₂alters IOP in N monkey eyes, when applied topically. A single 25 μl dosestudy was performed in 6 N and 8 G monkeys. IOP and pupil sizes weremeasured before and at 0 hr, 0.5 hr and then hourly for a total of 6 hrsafter 0.05% or 0.1% drug concentrations were administered. Tonographicoutflow facility (“C”) and fluorophotometric aqueous humor flow (F) weredetermined in 6 N monkeys before and after unilateral application of 25μl of 0.1% 8-iso PGE₂. In 8 G monkey eyes, 8-isoPGE₂ reduced IOP(p<0.005) up to 2 hrs or 5 hrs following administration of the 0.05% or0.1% concentration, respectively. The maximum reduction in IOP was4.6±0.8 (mean±SEM)mm Hg (0.05%) and 6.6±0.8 mm Hg (0.1%), as compared tobaseline measurements. After topical application of 8-iso PGE₂ the IOPwas lower (p<0.01) in the treated eyes of 6 N monkeys for 4 hrs, with amaximum difference of 3.2±0.2 mmHg, as compared to the fellowcontralateral control eyes. The pupil size was smaller (p<0.01) for 4hrs, up to 1.0±0.2 mm. Compared with vehicle-treated contralateralcontrol eyes, C was greater (p<0.005) by 48% at 2 hr after a single doseof 0.1% 8-iso PGE₂. F was unchanged (p<0.10) over a period of 4 hrsafter drug administration. Mild eyelid edema, conjunctival edema,hyperemia, and discharge appeared in some eyes treated with the 0.1%concentration.

Table 1A shows that 8-iso PGE₂ administrated to the normal monkey eyelowers IOP significantly by 20.3% and increases outflow facility by43.1%, an amount sufficient to account for the fall of IOP. By contrast,in Table 1B latanoprost in the normal monkey eye also lowers IOPsignificantly (by 10.8%), but the drug has not significant effect onoutflow facility. The lack of a major effect on outflow facility oflatanoprost in the primate eye is in agreement with studies in theliterature by other investigators.

TABLE 1 A. Effect of 0.1% 8-isoPGE₂ on Outflow Facility in 6 NormalMonkeys (2 hours after treatment) Intraocular Pressure Outflow FacilityMean ± SEM Mean ± SEM mmHg μl/ml/mmHg Treated eyes (drug) 13.0 ± 0.7*0.83 ± 0.10* Baseline 16.3 ± 1.1 0.58 ± 0.03 Control eyes (vehicle) 15.7± 0.5 0.56 ± 0.06 Baseline** 15.7 ± 0.6 0.51 ± 0.04 B. Effect of 0.005%latanoprost on Outflow Facility in 6 Normal Monkeys (1 hour aftertreatment) Intraocular Pressure Outflow Facility Mean ± SEM Mean ± SEMmmHg μl/min/mmHg Treated eyes (drug) 13.2 ± 0.7* 0.76 ± 0.08 Baseline14.8 ± 0.7 0.62 ± 0.07 Control eyes (vehicle) 15.0 ± 0.8 0.60 ± 0.07Baseline** 15.7 ± 0.3 0.73 ± 0.08 *Significantly different as comparedwith either baseline values or vehicle-treated eyes (two-tailed pairedt-test, p. < 0.05. **Baseline measurements made in the same monkeys atthe same time one day prior to drug treatments

Table 2 shows the effect of 8-iso PGE₂ on IOP and outflow facility inglaucomatous monkey eyes. Because of the individual variability inlaser-induced glaucomatous monkey eyes, the IOP and facilitymeasurements are expressed in the table as ratios (value of thedrug-treated eye+the value of the vehicle-treated eye). The ratios werecalculated from the values of the same glaucomatous monkey eyedetermined immediately prior to administration of the drug or thevehicle (time 0 hrs.), and the values at 2 hours after administration ofthe drug or vehicle. The data in Table 2 show that in the primate,administration of 8-iso PGE₂ to glaucomatous eyes significantly lowersIOP (by 13.8%) and significantly increases outflow facility (by 38.8%),which is of sufficient magnitude to account for the fall in IOP. Thusthe mechanism of lowering IOP by 8-iso PGE₂ in both normal andglaucomatous eyes is primarily due to an increase in aqueous humortrabecular outflow.

TABLE 2 Effect of 0.1% 8-iso PGE₂ on IOP Outflow Facility Responses in 8Glaucomatous Monkey Eyes (Unilateral) Intraocular Pressure Outflowfacility (drug-treated/ (drug-treated/ vehicle-treated) vehicle treated)Time 0 hr 2 hr 0 hr 2 hr Response Ratio (±SEM) 0.976 ± 0.843* ± 1.041 ±1.445** ± 0.002 0.0498 0.0498 0.161 % Change by drug — 13.8% — 38.8%decrease decrease Significantly different as compared to 0 hr, pairedt-test, p < 0.01*, <0.10**

EXAMPLE II

IOP was measured one hour before and at intervals up to six hours aftera single dose of 8-iso PGE, (the 13, 14 dihydro derivative of 8-isoPGE₂), 8-iso PGE₂, or 8-iso PGF_(2α) in laser-induced glaucomatous eyesin cynomolgus monkeys (wherein only one eye is rendered glaucomatous andthe other serves as a control). Following one day of baseline IOPmeasurement, a single 25 μl dose of either (i) 0.1 percent 8-iso PGE₁,or (ii) 0.1 percent 8-iso PGE₂, or (iii) 0.1 percent 8-iso PGF_(2α), wastopically applied to the glaucomatous eye in groups of 4 or 8 monkeys.It was found that 8-iso PGE₁ (0.1 percent) reduced IOP (p<0.05) for upto four hours in glaucomatous monkey eyes (n=4). The maximum reductionin IOP was 5.3±0.8 (mean SEM) mm Hg at 2 hours after dosing 8-iso PGE₂(0.1 percent) reduced IOP (p<0.05) for 5 hours with a maximum reductionin IOP of 6.6±0.8 mm Hg at 2 hours after dosing (n=8). After 0.1 percent8-iso PGF_(2α), a significant (p<0.05) reduction in IOP occurred only at1 hour with the maximum reduction in IOP of 3.3±0.9 mm Hg (n=4). Theresults are shown in Table 3. Based on these studies, of the compoundstested, 8-iso PGE₂ appears to have the greatest and 8-iso PGF_(2α), theleast activity in decreasing IOP in glaucomatous monkey eyes.

TABLE 3 Intraocular Pressure (treated - baseline) (mean mm Hg ± SEM) isoPG, 0.1% n 1 hr 2 hr 4 hr 6 hr 8-iso PGE₁ 4 −3.3 ± 1.3 −5.3 ± 0.8* −2.3± 0.5* −1.3 ± 0.9 8-iso PGE₂ 8 −4.5 ± 0.9** −6.6 ± 0.8** −2.9 ± 0.6**−1.2 ± 1.2 8-iso PGE_(2α) 4 −3.3 ± 0.8* −1.8 ± 1.1 −0.8 ± 1.7   0.3 ±0.5 *p < 0.05 **p < 0.005

Various publications are cited herein, the contents of which are herebyincorporated by reference in their entireties.

1. A method for decreasing intraocular pressure comprising administeringa therapeutically effective amount of an 8-iso prostanoid having thefollowing Formula I:

where bond W is selected from the group consisting of a single covalentbond and a double covalent bond, bond X is selected from the groupconsisting of a single covalent bond and a double bond, substituent Y isselected from the group consisting of a hydroxyl group having either αor β orientation relative to the five-membered ring and a keto function,and substituent Z is a hydrocarbon group selected from the group ofaliphatic, aromatic, or a combination of aliphatic and aromatichydrocarbon, to a patient in need of such treatment.
 2. The method ofclaim 1 wherein the 8-isoprostanoid is administered topically.
 3. Themethod of claim 2 wherein the 8-iso prostanoid is administered as acomposition comprising between 0.005 to 1 percent 8-iso prostanoid. 4.The method of claim 1, wherein the 8-iso prostanoid is selected from thegroup consisting of a compound having the following Formula II

or a derivative thereof.
 5. The method of claim 1, wherein the 8-isoprostanoid is selected from the group consisting of a compound havingthe following Formula III

or a derivative thereof.
 6. The method of claim 1, wherein the 8-isoprostanoid is selected from the group consisting of a compound havingthe following Formula IV

or a derivative thereof.
 7. The method of claim 2, wherein the 8-isoprostanoid is selected from the group consisting of a compound havingthe following Formula II

or a derivative thereof.
 8. The method of claim 2, wherein the 8-isoprostanoid is selected from the group consisting of a compound havingthe following Formula III

or a derivative thereof.
 9. The method of claim 2, wherein the 8-isoprostanoid is selected from the group consisting of a compound havingthe following Formula IV

or a derivative thereof.
 10. The method of claim 3, wherein 8-isoprostanoid is selected from the group consisting of a compound havingthe following Formula II

or a derivative thereof.
 11. The method of claim 3, wherein the 8-isoprostanoid is selected from the group consisting of a compound havingthe following Formula III

or a derivative thereof.
 12. The method of claim 3, wherein the 8-isoprostanoid is selected from the group consisting of a compound havingthe following Formula IV

or a derivative thereof.
 13. The method of claim 4, wherein thederivative is an ester derivative.
 14. The method of claim 5, whereinthe derivative is an ester derivative.
 15. The method of claim 6,wherein the derivative is an ester derivative.
 16. The method of claim7, wherein the derivative is an ester derivative.
 17. The method ofclaim 8, wherein the derivative is an ester derivative.
 18. The methodof claim 9, wherein the derivative is an ester derivative.
 19. Themethod of claim 10, wherein the derivative is an ester derivative. 20.The method of claim 11, wherein the derivative is an ester derivative.21. The method of claim 12, wherein the derivative is an esterderivative.
 22. A method for decreasing intraocular pressure comprisingadministering a therapeutically effective amount of an 8-iso prostanoidhaving the following Formula I:

where bond W is selected from the group consisting of a single covalentbond and a double covalent bond, bond X is selected from the groupconsisting of a single covalent bond and a double covalent bond andsubstituent Y is selected from the group consisting of a hydroxyl grouphaving either α or β orientation relative to the five-membered ring anda keto function, to a patient in need of such treatment.
 23. The methodof claim 22 wherein the 8-iso prostanoid is administered topically. 24.The method of claim 22 wherein the 8-iso prostanoid is administered as acomposition comprising between 0.005 to 1 percent 8 -iso prostanoid.